Malaria during pregnancy threatens the health of the mother and newborn. It causes maternal anemia, low birth weight, and infant mortality. In addition, pregnancy-associated malaria has long-lasting consequences on infant health that may be attributable to the effect of maternal malaria on the fetal immune system. Children born to mothers with placental malaria have increased risk of malaria in infancy. However, because these results are from observational studies, it cannot be determined if placental malaria alters susceptibility to malaria or whether infants born to women exposed to a heavy burden of malaria while pregnant will also be exposed to more malaria after birth. Another shortcoming of these studies is limiting the assessment of malaria during pregnancy to examination of the placenta at delivery. Peripheral malaria in pregnancy may also alter the infants' susceptibility to infection. The proposed mechanism for the effect of pregnancy-associated malaria on infant malaria susceptibility is malaria antigens crossing through the placenta into fetal circulation. This cause priming of the immune system and the induction of either immune tolerance or sensitization, with increased or decreased risk of malaria in infancy, respectively. However it is unknown what drives the infant's immune system towards tolerance versus sensitization. We hypothesize that chronic exposure to malaria antigens from placental malaria induces tolerance while transient exposure from maternal peripheral malaria induces sensitization. We have a unique opportunity to examine the effect of peripheral and placental malaria on infant risk of malaria through a clinical trial that will randomly apply interventions to alter fetal malaria exposure. In 2012, we began a randomized clinical trial of continuous prophylaxis versus intermittent treatment for malaria in pregnancy which will yield three distinct malaria exposure groups: (1) placental malaria; (2) peripheral malaria without placental infection; and (3) no malaria during pregnancy. In this proposed study, we will follow infants born to mothers in the clinical trial for the first ear of life conducting active and passive surveillance for malaria. In Aim 1 we hypothesize that children born to mothers with placental malaria will have the highest incidence of malaria in infancy, while children born to mothers with peripheral malaria will have the lowest incidence. In Aim 2 we hypothesize that children born to mothers with placental malaria will have a tolerogenic immune phenotype characterized by elevated T regulatory cells (Tregs), and immunosuppressive cytokines, while children born to mothers with peripheral malaria will have a sensitized immune phenotype characterized by elevated T effector cells and production of pro-inflammatory cytokines. We will use 12-parameter flow cytometry to rigorously identify Tregs from cord blood and cytometric bead array assays to determine the levels of cytokines in neonatal serum. We will determine the effect of maternal malaria on fetal immunity and infant susceptibility to malaria. With this new information, researchers and policy makers will be able to design new strategies to protect both pregnant women and newborns throughout the malaria-endemic world.